The goal of this research is to determine the physiological functions of PKA in vivo and assign specific roles to each of the 6 subunit genes in signal transduction. During the previous grant period, the principal investigator produced targeted mutations in each of the PKA subunits. The aims of the next grant period are to utilize these gene knockout mice in physiological and biochemical studies and to make further mutations in the PKA system. Specific goals are to determine the physiological and developmental changes which occur as a result of the Ca knockout, to characterize the tissue-specific expression and function of recently discovered C beta splice variants, to determine the role of RIa in embryonic development, to measure the physiological defects in fat metabolism in RIIbeta mutant mice, to characterize the role of PKA isozymes in neuronal gene induction, and to examine the functional significance of PKA anchoring. It is anticipated that mice carrying "genetic diseases" in the PKA pathway will provide a novel approach to understanding the physiological significance of the highly conserved PKA signaling system in mammals.